Treatment Considerations for Pulmonary Arterial Hypertension and Assessment of Treatment Response

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1 Treatment Considerations for Pulmonary Arterial Hypertension and Assessment of Treatment Response Robert P. Frantz, MD, FACC Professor of Medicine, Department of Cardiovascular Disease Director, Mayo Pulmonary Hypertension and Unexplained Dyspnea Clinics Mayo Clinic Rochester, MN Abstract: The process of considering initial treatment options for a patient with pulmonary arterial hypertension (PAH), implementing that treatment, and reassessing response can be conceived as a 7-step process. A patient-centered approach, conducted in the context of a pulmonary hypertension care team, implements these steps in a thoughtful and well-organized fashion. Step 1: Perform a thorough diagnostic evaluation Step 2: Consider patient PAH classification and comorbidities Step 3: Assess risk profile Step 4: Develop a nuanced understanding of patient goals and preferences Step 5: Create an initial treatment strategy Step 6: Implement a proactive longitudinal follow-up care plan Step 7: Adjust treatment approach based on clear metrics of effectiveness and tolerability The burgeoning array of treatment options for PAH provides the opportunity to tailor therapy to the needs of individual patients, but also demands that the clinician develop a cogent strategy for initiating therapy, monitoring therapeutic response, and addressing side effects of therapy. In this review, we seek to provide a practical framework for approaching this challenge. STEP 1: PERFORM A THOROUGH DIAGNOSTIC EVALUATION The path of many patients with pulmonary arterial hypertension (PAH) is fraught with persistently long duration of symptoms prior to proper evaluation, frequent misdiagnosis, excessively conservative initial therapy, or lack of recognition of worrisome disease progression necessitating additional treatment consideration. When pulmonary hypertension (PH) is suspected, evaluation at an accredited PH center of comprehensive care (CCC) or a PH regional clinical program (RCP) is strongly encouraged. Practitioners at these centers are passionate about meticulous evaluation, generally possess solid understanding of the complex physiology and hemodynamics of PH, and have the experience needed to avoid common pitfalls in diagnosis and therapy. In addition, the intensity of teamwork necessary to successfully initiate and manage longitudinal therapy cannot be overemphasized. These centers have devoted the necessary resources to achieve success, and have agreed to have their programs periodically reassessed by the Pulmonary Hypertension Association accreditation team. For patients outside the United States, the same principles apply: seek care at a center that has a strong track record of expertise in PH diagnosis and management. In many/most countries outside the United States, the government mandates that patients be seen at centers/networks established for a specific disease. Key Words longitudinal care, prognosis, pulmonary arterial hypertension Correspondence: frantz.robert@mayo.edu Disclosures: Dr Frantz has served as a consultant, advisory board member, or steering committee member for Actelion Pharmaceuticals US, Inc.; Arena Pharmaceuticals, Inc.; St. Jude Medical; Bayer Pharmaceuticals; and United Therapeutics Corporation. He has received institutional grant or research support from Actelion Pharmaceuticals US, Inc.; United Therapeutics Corporation; Gilead Sciences, Inc.; and the National Institutes of Health. STEP 2: CONSIDER PATIENT PAH CLASSIFICATION AND COMORBIDITIES Group 1 PAH includes a broad range of underlying diseases and pathophysiology that have important impact on prognosis, and tolerability and efficacy of the available treatment strategies. Comprehensive review of the entire spectrum of PAH is beyond the scope of this document, but several common considerations will be discussed. In addition, a variety of comorbid conditions require consideration. Table 1 provides a summary of therapeutic considerations relevant to the particular form of PAH that is being treated. Table 2 describes relevant comorbidities and implications. STEP 3: ASSESS RISK PROFILE Patients with PAH range from those who are highly vasoreactive and may do well for decades on calcium channel blockers, to those who present with advanced symptoms and overt right heart failure and should be immediately hospitalized for initiation of parenteral prostanoids. The majority of patients fall into intermediate categories, where there is more room for judgment about best approach, and a wider variety of decisions to be made. Monotherapy or combination therapy? Which agent(s) are most likely to be effective and well tolerated in a given patient scenario? 120 Advances in Pulmonary Hypertension Volume 16, Number 3; 2018

2 STEP 4: DEVELOP A NUANCED UNDERSTANDING OF PATIENT GOALS AND PREFERENCES A patient with newly diagnosed PAH is frequently frightened, upset, and stressed not a great environment for absorbing and processing complex information and making difficult decisions. Availability of information on the internet can in principle help the patient and family to be more informed, but unfortunately often results in additional anxiety when worst-case scenarios are envisioned. The expert PH center team should provide a calm and caring environment. While acknowledging the patient s distress, the team needs to provide a framework for discussion. This includes clear and succinct discussion of the diagnosis and categorization of risk, followed by an overview of the range of treatment options, likelihood of effectiveness, intrusiveness, and side effects. Coupled with development of an understanding of patient goals, this permits creation of a patient-centered treatment plan that is essential for the success of the process. STEP 5: CREATE AN INITIAL TREATMENT STRATEGY This strategy must integrate understanding of the patient s PAH subtype, comorbidities, risk profile, and goals of treatment. Patients should be classified into low-, intermediate-, or high-risk categories. At a minimum, components of initial risk stratification should include functional class, 6-minute walk distance, brain natriuretic peptide (BNP), or N-terminal pro-brain natriuretic peptide (NT-proBNP), right atrial pressure, cardiac index, and mixed venous oxygen saturation (Sv02). The 2015 European PH guidelines included these measures, in addition to the following: peak oxygen consumption and ventilation carbon dioxide production relationship (VE/VC02) ratio from cardiopulmonary exercise testing, right atrial area and presence or absence of pericardial effusion on echocardiography, clinical signs of right heart failure, progression of symptoms, and syncope in a proposed categorization of risk. 1 A retrospective study of newly diagnosed patients with idiopathic, heritable, or drug- and toxin-induced PAH enrolled in the French registry evaluated the prognostic value of defining how many of 4 low-risk criteria were met at the time of diagnosis, and at the time of first follow-up (median time to first follow-up 4.4 months). 2 Patients who had at least 3 low-risk criteria at baseline and first follow-up, or achieved at least 3 by first follow-up, had very good survival at up to 5 years follow-up. The low-risk criteria included: Table 1. Considerations relevant to specific subtypes of PAH PAH subtype Relevant considerations Therapeutic considerations Idiopathic Drug, toxin Genetic testing, screening of family Counseling if illicit drug use Familial Genetic testing, screening of family Aggressive treatment Connective tissue disease Rheumatology treatment, follow-up Assessment and treatment of associated interstitial lung disease Aggressive treatment Portopulmonary Hepatology treatment, follow-up Facilitation of liver transplant Congenital heart disease Congenital clinic treatment, followup Caution regarding intravenous therapy if shunt Functional class I-II 6-minute walk distance >440 m Right atrial pressure <8 mm Hg Cardiac index >2.5 L min-1 m-2 Interestingly, analysis of the subset of patients with BNP or NT-proBNP values at first follow-up demonstrated that inclusion of BNP <50 pg/ml or NT-proBNP <300 pg/ml as a low-risk marker resulted in the invasive markers dropping out of multivariable prediction. This is concordant with the REVEAL risk calculator, where proper utilization of a comprehensive battery of noninvasive risk markers largely eliminates the Table 2. Comorbidities relevant to PAH HFpEF risk factors Comorbidity Consideration Therapeutic implications Predisposition to fluid retention with PAH therapy Obesity Sleep-disordered breathing Sleep study, CPAP Hypoxemia, low DLCO Thyroid disorders Do chest CT? Associated parenchymal lung disease, PCH/PVOD Regular thyroid function testing Caution regarding endothelin antagonists. Proactive diuretics Overnight oximetry, exercise oxygen titration, caution regarding worsening hypoxemia with PAH therapy Iron-deficiency anemia Iron studies Replete iron; consider intravenous Rx Frailty, comorbidities limiting quality of life Careful discussion of goals Physical therapy, conservative Rx, palliative care consultation CPAP, continuous positive airway pressure; CT, computerized tomography; DLCO, diffusion lung capacity for carbon monoxide; HFpEF, heart failure with preserved ejection fraction; PCH, pulmonary capillary hemangiomatosis; PVOD, pulmonary veno-occlusive disease. Advances in Pulmonary Hypertension Volume 16, Number 3;

3 additional prognostic utility of invasive measures except at dramatically abnormal values. 3,4 This lends further credence to the concept that repeated invasive hemodynamics are likely not needed as often for prognostic purposes as may traditionally have been believed by some practitioners and experts. A similar analysis of the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) utilized up to 6 variables at baseline and first comprehensive follow-up (between 3 months and 2 years). This analysis also included a substantial number of patients with connective tissue disease. Each variable was graded 1-3 for low, intermediate, and high risk; the sum of the grades was divided by the number of available variables and rounded to the next integer to create a risk score of 1, 2, or 3. The variables and cutoff values are shown in Table 3. This scoring system reasonably separated the low-, intermediate-, and high-risk groups. Similar to the other described prognostication tools, the invasive parameters contributed relatively little to the performance of the model. An advantage of the REVEAL risk score is that it incorporates a more comprehensive set of variables that includes patient age, sex, diagnosis, renal impairment, heart rate, systolic blood pressure, BNP or NT-proBNP, pericardial effusion, DLCO, right atrial pressure, and pulmonary vascular resistance (the latter only adding information in situations of extreme elevation). It performs well in both newly diagnosed and prevalent patients, performs well even when some of the variables are not available, has been validated in separate cohorts, 6 and can be used longitudinally to track changing risk profiles. 4 Preliminary work suggests it could be useful as an endpoint in clinical trials. 7 An important lesson and recurring theme from multiple prognostication studies is that many patients are not treated aggressively despite intermediate or high-risk features, and despite the evolving data to indicate that more aggressive up-front or early combination therapy and more aggressive use of parenteral prostanoids in higher-risk patients is associated with improved outcomes. In this light, a few high-level recommendations should be considered when deciding on initial treatment options. Patients with very high-risk features should promptly be treated with parenteral prostanoids, usually combined with a phosphodiesterase 5 (PDE-5) inhibitor. Up-front triple combination therapy in high-risk patients with parenteral prostanoid, PDE-5 inhibitor, and endothelin receptor antagonist (ERA) has been reported to be remarkably effective in a case series. 8 Parenteral prostanoid therapy is the most potent treatment for PAH and offers the best chance of having a dramatic impact on hemodynamics over a sustained period. Inhaled treprostinil may be an optimal prostanoid choice for intermediate-risk patients with migraine headaches or intestinal issues or numerous drug intolerances. Intermediate-risk patients should usually be treated at a minimum with dual-combination oral therapy, most commonly with a PDE-5 inhibitor and ERA. This could be up front with ambrisentan and PDE-5 inhibitor or sequential with other agents. Low-risk patients can often be treated with sildenafil as monotherapy as the most cost-effective initial approach. However, it should be remembered that even some functional class II patients appeared to benefit from either up front or sequential combination therapy, 9,10 so patients treated with monotherapy should be followed closely to be sure their treatment is adequately meeting treatment goals. Scleroderma patients with symptomatic esophageal dysfunction may experience aggravation of symptoms with a PDE-5 inhibitor or riociguat. The combination of bosentan and sildenafil should generally be avoided since randomized, controlled studies have not confirmed efficacy of this combination, and there is pharmacokinetic interaction that may impact the efficacy. 11 STEP 6: IMPLEMENT A PROACTIVE LONGITUDINAL FOLLOW-UP CARE PLAN Initiation and Titration of Therapy This step includes selection of therapy, combined with regular telephone or secure messaging interactions with the PAH team, with the available resources of specialty pharmacy providers in conducting home- and telephone-based assessments. If diuretics are being utilized, then education regarding fluid and salt restriction, avoidance of nonsteroidal anti-inflammatory drugs, daily weight diary, and implementation of regular electrolyte testing is essential. Table 3. Variables and cutoff values for risk stratification in COMPERA analysis Low risk Intermediate risk High risk WHO FC I/II III IV 6-minute walk, m > <165 BNP, pg/ml < >300 NT-proBNP, pg/ml < >1400 Right atrial pressure < >14 Cardiac index 2.5 L min-1 m <2.0 Sv02, % > <60 FC, functional class; WHO, World Health Organization. In both of these studies, only a small number of patients reached the low-risk category, and some of the variables included are not validated but are instead derived from expert opinion. Reproduced with permission from the ERS Hoeper MM, Kramer T, Pan Z, et al. Mortality in pulmonary arterial hypertension: prediction by the 2015 European pulmonary hypertension guidelines risk stratification model. Eur Respir J. 2017;50(2): ; DOI: / Advances in Pulmonary Hypertension Volume 16, Number 3; 2018

4 Follow-up Visits For most newly diagnosed patients, a PH center follow-up visit at 3 months after initiation of therapy is appropriate. For the first year, every 3 months is a reasonable starting point for follow-up, stretching out to every 6 months thereafter if treatment goals have been achieved. Interim contact by telephone or secure messaging should be encouraged, so that symptoms of disease progression, issues of treatment tolerability, insurance dilemmas, or compliance are not overlooked. It never feels good to see a patient back, find they are deteriorating and/or discontinued their treatment, and realize it may have been preventable if the follow-up had been more frequent. For patients not achieving treatment goals, proactive adjustments in approach and continued frequent follow-up are recommended. Alternating visits with a PH CCC and a PH RCP for patients with moderate to high risk can work well clinically, helps provide patients with access to evolving treatments and research opportunities, and allows timely decision making regarding transplantation. Components of recommended follow-up are shown in Table 4. STEP 7: ADJUST TREATMENT APPROACH BASED ON CLEAR METRICS OF EFFECTIVENESS AND TOLERABILITY Pulmonary arterial hypertension is a tricky condition; it can respond beautifully to initial therapy, or worsen rather inexplicably. The wise practitioner gathers the broad range of clues at each follow-up visit that permit an updated snapshot of degree of compensation. The BNP or NT-proBNP level is often a convenient starting point; in a given patient, the trends in those values paint a picture that can be supported or refuted by other aspects of the patient assessment. If the value is normal or nicely downtrending, most often the other prognostic markers fall in line. An exception is the patient with major obesity, where low levels may not be representative of RV compensation, and in renal insufficiency, where levels can be high due to the renal insufficiency and may or may not be trending with RV compensation. My personal approach is to look at the NT-proBNP level, then the echo, with global subjective attention to RV size and function, extent of deformation of the ventricular septum, size of the left ventricular cavity, combined with objective measures (tricuspid annular plane systolic excursion, RV strain if available, estimated right atrial pressure based on inferior vena cava assessment, and estimated pulmonary artery pressure), severity of tricuspid regurgitation, and presence or absence of pericardial effusion. I then look at the 6-minute walk test including distance walked, heart rate and blood pressure response, oxygen saturations, and Borg dyspnea scores. For a subset of patients with quite well preserved 6-minute walk distance but with moderate or severe PAH, serial cardiopulmonary exercise testing is useful in providing a better sense of any changes in RV reserve. With these elements in mind, I then greet the patient and any accompanying family, ask an open-ended question, and listen. How is their PAH or its treatment impacting their daily lives? What is their functional class, and has it changed? Are there any evolving signs or symptoms of right heart failure or circulatory insufficiency? Is their therapy reasonably tolerated, or unacceptably intrusive or fraught with side effects? Do their symptoms Table 4. Components of recommended follow-up and exam results fit with the objective tests? This integration of the history, physical exam, testing, and input of the family informs additional steps. Input of the PH nursing team both to visit with the patient to get up to date with tolerability and adequacy of current therapy, and to assist with troubleshooting medication side effects or infusion system and site concerns is extremely useful. If all seems stable, treatment goals have been achieved, and the treatment is reasonably tolerated, then no change in treatment plan is necessary. If things don t fit, then perhaps it is time to repeat a right heart catheterization. If the patient is in the titrating phase of parenteral prostanoids, then repeat catheterization to reassess hemodynamics including careful assessment of cardiac output should be done, particularly when what is viewed as potential maintenance dose is achieved. KEY POINT For patients not achieving treatment goals despite a typical approach such as PDE-5 inhibitor plus ERA, it is critical to comprehensively reassess risk profile and the trajectory of the clinical course. Parenteral prostanoids should be added if there are evolving higher-risk features and there is a desire for an aggressive approach. This is the path Assessment 3 months 6 months 12 months Functional class R R R BNP or NT-proBNP R R R 6-minute walk R R R RV-centric echocardiogram C R R Cardiopulmonary exercise C C Right heart catheterization C C C Electrolytes, CBC, LFT R R R Thyroid function R R Chest x-ray Electrocardiogram C R Pulmonary function, DLCO C R Overnight oximetry Palliative care C C C, consider; CBC, complete blood count; LFT, liver function test; R, recommended; RV, right ventricle. C C Advances in Pulmonary Hypertension Volume 16, Number 3;

5 most likely to be successful in achieving treatment goals rapidly and in a sustainable fashion. Particularly for patients at intermediate risk where the decision to add therapy is part of a proactive earlier intervention strategy, options include: Switch PDE-5 inhibitor to riociguat 12 Add selexipag 13,14 or inhaled treprostinil 14 (note that this study added treprostinil to monotherapy; there are no randomized, controlled data of triple-combination therapy with inhaled treprostinil, PDE-5 inhibitor, and ERA, but clinical experience suggests that it can be effective) Add oral treprostinil (there are no conclusive randomized data to support this approach; thus far the only positive randomized, controlled trial is as monotherapy) For stable patients receiving inhaled treprostinil who wish to convert to an all-oral program, there is preliminary short-term evidence that switching to selexipag is successful with some but not all of them 15 ; direct long-term comparative efficacy data are not available For patients not tolerating selexipag or oral treprostinil, switching to inhaled treprostinil can largely avoid systemic prostanoid side effects CONCLUSION Initial and longitudinal care of patients with PAH requires a thorough understanding of each patient s goals and preferences, their particular PAH phenotype and prognosis, and the pros and cons of the available treatment options. A 7-step team-based approach is described that provides a blueprint for success in the care of these compelling, complex, and brave patients. References 1. Galiè N, Humbert M, Vachiery JL, et al ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37(1): Boucly A, Weatherald J, Savale L, et al. Risk assessment, prognosis and guideline implementation in pulmonary arterial hypertension. Eur Respir J. 2017;50(2). 3. Benza RL, Gomberg-Maitland M, Miller DP, et al. The REVEAL Registry risk score calculator in patients newly diagnosed with pulmonary arterial hypertension. Chest. 2012;141(2): Benza RL, Miller DP, Foreman AJ, et al. Prognostic implications of serial risk score assessments in patients with pulmonary arterial hypertension: a Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) analysis. J Heart Lung Transplant. 2015;34(3): Hoeper MM, Kramer T, Pan Z, et al. Mortality in pulmonary arterial hypertension: prediction by the 2015 European pulmonary hypertension guidelines risk stratification model. Eur Respir J. 2017;50(2). 6. Sitbon O, Benza RL, Badesch DB, et al. Validation of two predictive models for survival in pulmonary arterial hypertension. Eur Respir J. 2015;46(1): Benza RL, Farber HW, Frost A, et al. REVEAL risk scores applied to riociguat-treated patients in PATENT-2: Impact of changes in risk score on survival. J Heart Lung Transplant Nov 11. [Epub ahead of print] 8. Sitbon O, Jaïs X, Savale L, et al. Upfront triple combination therapy in pulmonary arterial hypertension: a pilot study. Eur Respir J. 2014;43(6): Galiè N, Barberà JA, Frost AE, et al; AMBI- TION Investigators. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. N Engl J Med. 2015;373(9): Pulido T, Adzerikho I, Channick RN, et al; SERAPHIN Investigators. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369(9): McLaughlin V, Channick RN, Ghofrani HA, et al. Bosentan added to sildenafil therapy in patients with pulmonary arterial hypertension. Eur Respir J. 2015;46(2): Hoeper MM, Simonneau G, Corris PA, et al. RESPITE: switching to riociguat in pulmonary arterial hypertension patients with inadequate response to phosphodiesterase-5 inhibitors. Eur Respir J. 2017;50(3). 13. Sitbon O, Channick R, Chin KM, et al; GRIPHON Investigators. Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2015;373(26): McLaughlin VV, Benza RL, Rubin LJ, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol. 2010;55(18): Frost A, Janmohamed M, Fritz J, et al. Tolerability and safety of transition from inhaled treprostinil to oral selexipag in pulmonary arterial hypertension: Results from the TRANSIT-1 study. Am J Respir Crit Care Med. 2017:A Advances in Pulmonary Hypertension Volume 16, Number 3; 2018